1. Field of the Invention
The present invention relates to a 4-fluorobiphenyl derivative of formula (I), which is useful as a cholesterol lowering agent or a lipid lowering agent because of its strong inhibitory effect on a 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hereinafter referred to as HMG-CoA reductase) thereof: ##STR5## wherein A is a .omega.-oxycarbonyldihydroxybutyl group of formula (II): ##STR6## wherein R.sup.2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, which may have a substituent, an alkaline metal or an alkaline earth metal; or a tetrahydropyranyl group of formula (III): ##STR7## R.sup.1 is an alkyl group having 1 to 6, substituted with a heteroaromatic group, an alkoxyalkyl group, or a hydroxyalkyl group.
2. Discussion of Background
ML-236B (Mevastatin) has been discovered in the form of a fungal metabolite, which is a compound capable of lowering the concentration of cholesterol in the blood, which is considered to be a prominent factor for causing arteriosclerosis (refer to Japanese Laid-Open Patent Application 50-155690). ML-236B, however, has not yet been clinically used.
The effect of lowering the concentration of cholesterol in the blood exhibited by ML-236B is based on its competitive inhibitory effect on HMG-CoA reductase which serves as a rate-determining enzyme for the biosynthesis of cholesterol.
ML-236B is a compound constructed in such a manner that a hexahydronaphthalene skeleton is bonded to the .omega.-position of 3,5-dihydroxyheptanoic acid, and it is understood that the 3,5-dihydroxyheptanoic moiety is an indispensable moiety for the generation of the inhibitory effect on the HMG-CoA Reductase.
After the discovery of ML-235B, compounds such as prevastatin (refer to Japanese Laid-Open Patent Application 57-2240), simvastatin (refer to U.S. Pat. No. 4,444,784)) and lovastatin (refer to U.S. Pat. No. 4,231,938) have been discovered and are used clinically in practice. These compounds are considered as such compounds that substituents of the hexahydronaphthalene ring of ML-236B are partially modified biochemically or chemically.
Furthermore, varieties of compounds have been synthesized in an attempt to obtain compounds having higher HMG-CoA reductase inhibitory effect than those of drugs such as pravastatin, simvastatin, and lovastatin, for instance, as disclosed in Japanese Laid-Open Patent Application 56-45470, U.S. Pat. No. 4,375,475, Japanese Laid-Open Patent Application 58-8076, U.S. Pat. Nos. 4,459,422, 4,710,513, 4,567,289, 4,812,583, and German Laid-Open Patent 3909278.
The above-mentioned simvastatin and lovastatin exhibit a strong cholesterol lowering effect. However, it has been reported that these compounds also exhibit side effects such as myositis and sleep disorder (refer to Am. J. Cardiol., 62, 28J(1988); 66, 11B(1990); 65, 23F(1988); N. Eng. J. Med., 319(18)1222(1988); Br. Med. J., 30, 669(1990)).
It is considered that one of the factors for causing such side effects is the organotropism of these drugs. To be more specific, pravastatin, which is highly water-soluble, is not incorporated into histoblasts other than those of liver. In contrast to this, simvastatin and lovastatin which are highly lipid-soluble are transferred into both liver cells and non-liver cells, so that myositis and sleep disorder are caused.
It is recognized that simvastatin has an advantage over pravastatin that it has an antiarteriosclerosis effect because of its cytostatic function with respect to the cells of smooth muscles.
In view of these facts, a new HMG-CoA reductase inhibiting agent having an appropriate water-solubility, which is positioned between the two opposite extreme water-solubilities of simvastatin (lovastatin) and pravastatin is desired.
With respect to varieties of compounds which have been synthesized after the development of pravastatin, simvastatin, and lovastatin, their water-solubility and lipid-solubility upon which the generation of the previously mentioned side effects depends, have not been studied.
A compound which can be satisfactorily used as an effective component for a cholesterol lowering agent or a lipid lowering agent has not yet been discovered.